Abstract
Nerve injury-induced neuropathic pain is difficult to treat and mechanistically characterized by strong neuroimmune interactions, involving signaling lipids that act via specific G-protein coupled receptors. Here, we investigated the role of the signaling lipid receptor G2A (GPR132) in nerve injury-induced neuropathic pain using the robust spared nerve injury (SNI) mouse model. We found that the concentrations of the G2A agonist 9-HODE (9-Hydroxyoctadecadienoic acid) are strongly increased at the site of nerve injury during neuropathic pain. Moreover, G2A-deficient mice show a strong reduction of mechanical hypersensitivity after nerve injury. This phenotype is accompanied by a massive reduction of invading macrophages and neutrophils in G2A-deficient mice and a strongly reduced release of the proalgesic mediators TNFα, IL-6 and VEGF at the site of injury. Using a global proteome analysis to identify the underlying signaling pathways, we found that G2A activation in macrophages initiates MyD88-PI3K-AKT signaling and transient MMP9 release to trigger cytoskeleton remodeling and migration. We conclude that G2A-deficiency reduces inflammatory responses by decreasing the number of immune cells and the release of proinflammatory cytokines and growth factors at the site of nerve injury. Inhibiting the G2A receptor after nerve injury may reduce immune cell-mediated peripheral sensitization and may thus ameliorate neuropathic pain.
Highlights
Neuropathic pain is a form of chronic pain induced by lesions, diseases, chemicals or tumor invasion of the somatosensory nervous system [1,2]
We previously showed that activation of G2A in sensory neurons leads to an increased mechanical pain hypersensitivity during oxaliplatin-induced neuropathic pain due to sensitization of transient receptor potential vanilloid 1 (TRPV1) [16]
Since peripheral nerve injury-induced neuropathic pain is characterized by a strong immune cell infiltration from day 4, ongoing and lasting for over 21 days [40,41], we chose the robust spared nerve injury (SNI) model [27]
Summary
Neuropathic pain is a form of chronic pain induced by lesions, diseases, chemicals or tumor invasion of the somatosensory nervous system [1,2]. Thereby, the normally high thresholds of peripheral nociceptors to mechanical and thermal stimuli are drastically reduced [9,11,12,13] This peripheral sensitization is caused by neuroimmune interactions involving migration and infiltration of immune cells to the site of injury and the release of proinflammatory factors in nerve injury-induced neuropathic pain [6,11,14]. This interaction is known to modulate neuronal ion channels, such as the transient receptor potential vanilloid 1 (TRPV1) channel, thereby altering pain perception during neuropathic pain [6,12,13]. G2A belongs to the group of proton-sensing GPCRs and is expressed in TRPV1-positive primary sensory neurons, but mainly in immune cells [18,19]
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